Myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are chronic myeloid malignancies characterized by overproduction of myeloid lineage cells. An acquired JAK2V617F mutation, which results in constitutive activation of the JAK2 tyrosine kinase, has been found in a majority of patients with MPNs. This has led to the development of JAK2 inhibitors. Ruxolitinib, a JAK1/JAK2 inhibitor, has been approved for treatment of hydroxyurea-resistant PV and advanced MF. Although Ruxolitinib therapy can reduce splenomegaly and constitutional symptoms, it failed to produce complete remission in patients with PV/MF. It has become clear that current chemotherapies including JAK2 inhibitors are not sufficient to cure MPNs. So, there is a critical need to develop novel targeted therapies for MPNs. We have found that SHP2 is constitutively phosphorylated/activated in mouse and human MPN cells expressing JAK2V617F. SHP2 is a protein tyrosine phosphatase that plays a positive role in cell signaling. In preliminary studies, we have observed that knockdown of SHP2 significantly inhibits proliferation of cells expressing JAK2V617F. Moreover, deletion of SHP2 inhibits the development of PV and MF in JAK2V617F knock-in mice. Furthermore, treatment with a novel SHP2 inhibitor 11a-1 significantly inhibits the growth of JAK2V617F-positive MPN cells. So, we hypothesize that SHP2 may play important roles in hematopoietic transformation/MPNs induced by JAK2V617F, and pharmacologic inhibition of SHP2 might be efficacious against MPNs. To test our hypothesis, we have proposed two specific aims. In Aim 1, we will further define the role of SHP2 in the development and maintenance of PV and MF using floxed SHP2 and conditional JAK2V617F knock-in mice. In Aim 2, we will determine the safety and efficacy of a novel SHP2 inhibitor 11a-1 against cultured and primary MPN cells and animal models of PV and MF. We will also determine the effects of SHP2 deletion or inhibition on JAK2V617F-evoked signaling and define the mechanism by which SHP2 regulates JAK2V617F-induced transformation/MPNs. Our proposed studies will provide the first demonstration that SHP2 plays an important role in the development of MPNs (PV and MF) and targeting of SHP2 using small molecule inhibitor 11a-1 is a novel strategy in treating MPNs. Moreover, results from these pre-clinical studies will generate the supportive data for Phase I/II clinical trials of SHP2 inhibitor 11a-1 in the treatment of MPNs.